Abstract
High salt (HS) intake sensitizes central autonomic circuitry leading to sympathoexcitation. However, its underlying mechanisms are not fully understood. We hypothesized that inhibition of PVN endoplasmic reticulum (ER) Ca2+ store function would augment PVN neuronal excitability and sympathetic nerve activity (SNA). We further hypothesized that a 2% (NaCl) HS diet for 5 weeks would reduce ER Ca2+ store function and increase excitability of PVN neurons with axon projections to the rostral ventrolateral medulla (PVN-RVLM) identified by retrograde label. PVN microinjection of the ER Ca2+ ATPase inhibitor thapsigargin (TG) increased SNA and mean arterial pressure (MAP) in a dose-dependent manner in rats with a normal salt (NS) diet (0.4%NaCl). In contrast, sympathoexcitatory responses to PVN TG were significantly (p < 0.05) blunted in HS treated rats compared to NS treatment. In whole cell current-clamp recordings from PVN-RVLM neurons, graded current injections evoked graded increases in spike frequency. Maximum discharge was significantly augmented (p < 0.05) by HS diet compared to NS group. Bath application of TG (0.5 μM) increased excitability of PVN-RVLM neurons in NS (p < 0.05), yet had no significant effect in HS rats. Our data indicate that HS intake augments excitability of PVN-RVLM neurons. Inhibition of the ER Ca2+-ATPase and depletion of Ca2+ store likely plays a role in increasing PVN neuronal excitability, which may underlie the mechanisms of sympathoexcitation in rats with chronic HS intake.
Highlights
Elevated dietary salt intake is a major contributor to the pathogenesis of cardiovascular disease (Appel et al, 2011; Kotchen et al, 2013; Oh et al, 2016)
In order to determine the contribution of the paraventricular nucleus (PVN) neuronal ER Ca2+ stores in regulating sympathetic nerve activity (SNA) and arterial blood pressure (ABP), we performed bilateral microinjection of TG into the PVN
The PVN is a key regulatory center for SNA, and disinhibition of PVN neurons contributes to the augmented sympathetic outflow in neurogenic HTN
Summary
Elevated dietary salt intake is a major contributor to the pathogenesis of cardiovascular disease (Appel et al, 2011; Kotchen et al, 2013; Oh et al, 2016). Accumulating evidence indicates that the adverse effects of excess dietary salt on cardiovascular function may be independent of changes in arterial blood pressure (ABP) (Frohlich, 2007; Stocker et al, 2010; Appel et al, 2011; Kotchen et al, 2013; Cook et al, 2014). The central nervous system is an important mediator of cardiovascular disease including salt-sensitive hypertension through augmented sympathetic nerve activity (SNA) (King et al, 2007; Osborn et al, 2007; Elijovich et al, 2016). Salt Diet and Sympathetic Nervous System exaggerated SNA and ABP responses to stimuli in normotensive rats (Pawloski-Dahm and Gordon, 1993; Ito et al, 1999; Adams et al, 2007, 2008, 2009; Simmonds et al, 2014). Studies have demonstrated that enhanced PVN neuronal activity supports the augmented SNA in several models of neurogenic hypertension (HTN) (Herzig et al, 1991; Allen, 2002; Bardgett et al, 2014); little is known regarding the effects of dietary salt on PVN neuronal excitability in normotensive animals
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